Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States. Despite recent advances in understanding of aberrantly functioning signaling pathways involved in lung cancer development, the master regulator transcription factors affected by these altered signaling pathways that regulate the expression of critical genes involved in the growth and survival of lung cancer cells are still poorly understood. The transcription factor cyclic adenosine 3',5'- monophosphate-response element-binding protein (CREB) regulates the expression of numerous genes involved in cancer development and has been shown to play an important role in the proliferation, survival, and differentiation of several cell types. Recently, we found that CREB plays a role in the transdifferentiation and maintenance of the normal mucociliary phenotype of bronchial epithelial cells. In addition, CREB was expressed at significantly higher levels and more active in several non-small cell lung cancer (NSCLC) cell lines than in primary normal human tracheobronchial epithelial cells and in human lung squamous cell carcinoma and adenocarcinoma tissue than in paired adjacent normal lung tissue. Retrospective survival- duration analysis of patients with NSCLC showed that overexpression of the active form of CREB was a negative prognostic factor. Moreover, we observed that treatment with genetic and chemical inhibitors that blocked the expression and activation of CREB dramatically suppressed the growth and survival of NSCLC cells. In summary, our preliminary findings suggest that CREB is a critical molecule that controls both the normal differentiation of bronchial epithelial cells and the abnormal growth of lung cancer cells. Based on our findings, we hypothesize that aberrantly regulated CREB plays a critical role in the abnormal proliferation and survival of NSCLC cells. To test this hypothesis, we will pursue three specific aims: 1. To determine whether CREB promotes the pathogenesis of NSCLC by analyzing preneoplastic NSCLC lesions and modulating CREB expression and activity in an in vitro lung carcinogenesis model cell and in vivo animal models. 2. To identify the biologic and molecular consequences of modulating CREB activity using small molecule inhibitors in lung cancer development. 3. To establish the genetic role of CREB in the development of lung cancer. These studies will increase our understanding of the mechanisms of abnormal survival and proliferation of NSCLC cells, in particular, the role of CREB in lung cancer development. We are hopeful that this study will identify a novel target for preventive and/or therapeutic strategies in patients with NSCLC.

Public Health Relevance

Lung cancer is the most common form of cancer in the world and the leading cause of cancer-related deaths in both men and women in the United States, despite of the recent advances in development of new therapeutic targets and methods. The transcription factor cyclic adenosine 3',5'-monophosphate-response element-binding protein (CREB) regulates numerous genes involved in cancer development. In addition to our earlier studies demonstrated that CREB is a critical molecule that controls both the normal differentiation of bronchial epithelial cells and the abnormal growth of lung cancer cells, the proposed studies will substantially enhance our understanding of the mechanisms of abnormal survival and proliferation of lung cancer cells and facilitate to identify a novel target for preventive and/or therapeutic strategies in patients with lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA126801-05
Application #
8546983
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Ault, Grace S
Project Start
2010-04-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$319,416
Indirect Cost
$127,430
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Saintigny, Pierre; Massarelli, Erminia; Lin, Steven et al. (2013) CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma. Cancer Res 73:571-82